Intramolecular Cyclization of Azido-Isocyanides Triggered by the Azide Anion: An Experimental and Computational Study

This work describes the unprecedented intramolecular cyclization occurring in a set of α-azido-ω-isocyanides in the presence of catalytic amounts of sodium azide. These species yield the tricyclic cyanamides [1,2,3]triazolo[1,5-a]quinoxaline-5(4H)-carbonitriles, whereas in the presence of an excess of the same reagent, the azido-isocyanides convert into the respective C-substituted tetrazoles through a [3 + 2] cycloaddition between the cyano group of the intermediate cyanamides and the azide anion. The formation of tricyclic cyanamides has been examined by experimental and computational means. The computational study discloses the intermediacy of a long-lived N-cyanoamide anion, detected by NMR monitoring of the experiments, subsequently converting into the final cyanamide in the rate-determining step. The chemical behavior of these azido-isocyanides endowed with an aryl-triazolyl linker has been compared with that of a structurally identical azido-cyanide isomer, experiencing a conventional intramolecular [3 + 2] cycloaddition between its azido and cyanide functionalities. The synthetic procedures described herein constitute metal-free approaches to novel complex heterocyclic systems, such as [1,2,3]triazolo[1,5-a]quinoxalines and 9H-benzo[f]tetrazolo[1,5-d][1,2,3]triazolo[1,5-a][1,4]diazepines.


■ INTRODUCTION
Isocyanides are versatile building blocks in organic chemistry. 1he unique properties of isocyanides come from their formally divalent carbon, which endow them with the ability to react with nucleophiles and electrophiles yielding respective αadducts. 2−8 Azides are also valuable intermediates in organic synthesis. 9They have found new applications in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. 10Recently, the Staudinger ligation protocol based on the reactivity of azides with phosphanes has found a relevant place in the field of bioorthogonal chemistry. 11he inclusion of both isocyanide and azide functionalities in the same molecule allows to combine the reactivity of these two groups in an orthogonal manner.−14 Within this type of bifunctional compounds, 1-azido-2-isocyanoarenes are the most studied.
−18 The reaction of 1-azido-2-isocyanoarenes with phenylacetaldehyde/ DBU and further treatment with the Togni reagent yields [1,2,3]triazolo [1,5-a]quinoxalines. 19 Benzimidazoles can also be synthesized from 1-azido-2-isocyanoarenes and diphenyl phosphine in the presence of manganese(II) acetate 20 or by reaction with diazonium salts. 20ollowing our report on an easy entry into heterocyclic building blocks for drug discovery, 21 we envisioned that a similar synthetic methodology could give us access to new scaffolds endowed with isocyanide and azide functionalities adequately placed for reacting one another in an intramolecular way, thus yielding complex nitrogenated heterocycles.To our knowledge, there is only one reported example of azidoisocyanides in which both functional groups participate in metal-free intramolecular reactions, the intramolecular cyclization of 2-[1-azidobenzyl]-1-isocyanobenzene in the presence of sodium hydride to give 4-phenylquinazoline. 22In order to discover new intramolecular cyclizations involving both functional groups, we designed azido-isocyanides 1 with an aryl-triazolyl moiety as the linker of both functionalities (Scheme 1).
At the start of the present investigations, we envisaged two putative reaction paths between the azido and isocyano functions of compounds 1 (Scheme 1), either a [3 + 2]  cyclization to give presumably unstable carbenes 2 or an alternative [3 + 1] cyclization by α-addition of the azido group to the carbon atom of the isocyanide to give fused triazetimines 3 or cyclic carbodiimides 4 by further N 2 extrusion.These two reaction paths are unprecedented, as well as its reaction intermediates and products.
Before carrying out the synthetic experiments, we performed an exploratory computational study for testing the ability of compound 1a (R = H, Scheme 1) to undergo those cyclizations.The results of the computations showed that carbene 2a is highly unstable and we failed in all the attempts to locate the transition structure of the intramolecular [3 + 2]  process.However, the alternative [3 + 1] cyclization to give 3a and its subsequent transformation into the carbodiimide 4a by loss of nitrogen seem to be feasible provided the reaction is conducted under strong thermal conditions (see the Supporting Information).
Herein, we disclose our results on the synthesis of azidoisocyanides 1 which proved to be not so simple as anticipated and that laterally led to novel complex heterocyclic systems.

■ RESULTS AND DISCUSSION
The route toward azido-isocyanides 1 started with the synthesis of intermediates 7a−d by the reaction of 1-azido-2isocyanoarenes 5a−d 19 with the α-ketophosphorane 6 (Table 1).This methodology for preparing 1,2,3-triazoles, originally described by Harvey, 23 and L'Abbe, 24 is based on the 1,3dipolar cycloaddition of the azido group to the double bond of the betainic form of 6 and further elimination of triphenylphosphine oxide.By using this procedure, the resulting 1,5-disubstituted 1,2,3-triazoles 7a−d were obtained in medium to good yields (Table 1).
Obviously we expected that the azido-isocyanide 1b (Scheme 2) would be readily available from the 5chloromethyl triazole 7b by chloride substitution with the azido anion. 10However, when 7b was treated with sodium azide in dimethylformamide (DMF) at 60 °C for 24 h, thinlayer chromatography (TLC) analysis (silica gel, 1:2 AcOEt/ hexane) showed the formation of a new main product but also apparently a residual spot of starting material.Hence, the reaction mixture was further stirred at 80 °C for an additional period of 48 h.Even though the conversion seemed still uncomplete by TLC, we proceeded to isolate the two species (work-up consisting of water addition and further extraction with AcOEt).The less polar compound turned out to be not the starting material but the pursued azidomethyl triazole 1b.Surprisingly, the 13 C NMR spectrum of the second, more polar species showed the disappearance of the peak around 170 ppm attributable to the isocyanide carbon atom (172.2 ppm in 7b) and the rise of a new quaternary peak at 112.9 ppm.In its infrared (IR) spectrum, the lack of the typical bands assignable to the isocyanide and azide functions close to 2100 cm −1 as well as the appearance of a band at 2220 cm −1 gave us a first indication of the formation of a cyanamide fragment at the expense of the azido and isocyano groups, a hint that was confirmed by the unequivocal structural determination of this second product as 8b with the aid of X-ray crystallography (Scheme 2 and Figure 1).The Journal of Organic Chemistry Afterward, under smoother reaction conditions (treatment of 7b with sodium azide in DMF at 25 °C), the 5-azidomethyl triazole 1b was obtained in 93% yield (Table 2, entry 2).This reaction is general for the 5-chloromethyltriazoles 7a−d, and thus, the azido-isocyanides 1a−d were obtained in yields ranging 52−93% (Table 2).
Next, we studied the serendipitous formation of cyanamide 8b and the role of sodium azide in that process (Table 3).
First, we checked the thermal stability of azido-isocyanide 1b by heating in DMF solution at 120 °C for 48 h.Under these conditions, the starting material was recovered unaltered (Table 3, entry 1), thus discarding our previous expectations summarized in Scheme 1. Afterward, we reacted 1b with one equivalent of sodium chloride, a secondary product in the reaction of 7b with sodium azide, in DMF at 60−80 °C for 48 h.Once again, no reaction took place (Table 3, entry 2).We conducted three more experiments in the presence of 0.5, 1.0, and 1.5 equiv of sodium azide, thus obtaining cyanamide 8b in yields ranging 34−67% (Table 3, entries 3−5).These assays not only confirmed the key role of sodium azide in the formation of cyanamide 8b but also the advantage of using sub-stoichiometric amounts of this reagent to maximize the yield of the conversion 1b → 8b.
To gain further insights into this process, we monitored the reaction of 1b in the presence of 0.5, 1.0 and 1.5 equiv of sodium azide by 1 H NMR spectroscopy (Figure 2, Scheme 3, and Table 4).In the presence of 0.5 equiv of NaN 3 (DMF-d 7 , 80 °C) the cyanamide 8b is neatly apparent in the reaction mixture (blue peaks) after 48 h (Figure 2).However, resonances for two new products also appear in this spectrum (red and green peaks).The red peaks weaken over time and totally disappeared after 7 days.These peaks were assigned to a long-lived intermediate (LLI) prior to the formation of 8b (Scheme 3).Remarkably, the resonances of the aromatic protons of LLI are considerably shifted to lower chemical shifts compared to those of 1b and 8b.The green-colored signals increase over time and become the most intense ones after 7 days (Figure 2 and Table 4, entry 2).
These green-colored signals were assigned to the N-2 tautomer of the tetrazole 9b (see below), which presumably would form through a 1,3-dipolar cycloaddition between the azide anion and the cyano group of 8b followed by protonation. 25,26According to this hypothesis, the proportion of tetrazole 9b in the mixture increases when the reaction is conducted with greater amounts of sodium azide (Table 4, entries 3−5).In fact, 9b was the exclusive reaction product after 7 days in the presence of 1.5 equiv of this reagent (Table 4, entry 6) (for a complete picture of the three monitoring experiments see Figures S3−S5 in the Supporting Information).
Two additional experiments confirmed that tetrazole 9b formed by the reaction of 8b with NaN 3 and not from a common precursor of both species 8b and 9b.Thus, 8b was heated at 80 °C in DMF-d 7 in either lack or presence of sodium azide (1.0 equiv).In the first experiment, 8b was recovered unaltered, whereas in the second one tetrazole 9b quantitatively formed.At this point, we wondered why we neither detect 9b in the reaction media nor isolated it when conducting the reaction in a flask-scale (Scheme 2).We reasoned that due to the high acidity of tetrazole derivatives, with pK a values around 5, 27,28 and without an acidic work-up (see above), 9b should remain in the aqueous phase in the form of its conjugated base, not being transferred into the organic phase and thus avoiding its detection in the TLC analyses of this phase.
The identity of 9b was confirmed by 2D NMR (HMBC, HSQC and NOESY, see the Supporting Information).Moreover, computational methods, combined with the experimental NMR data, allowed us to determine the tautomeric form of the tetrazole ring, N-1 or N-2, present in its DMSO-d 6 solution (Scheme 3). 29Thus, the 1 H and 13 C NMR data of 9b were compared with those calculated from the corresponding geometry optimized structures of both tautomeric forms (Supporting Information). 30The best fit between theoretical and experimental data was found for the N-2 tautomer and the most revealing information is the chemical shift of the carbon atom at the tetrazole ring, 164.4 ppm (calculated) and 163.6 ppm (experimental), far enough from the calculated value for the N-1 tautomer, 155.3 ppm. 31

The Journal of Organic Chemistry
Moreover, the observed chemical shift of this carbon atom agrees well with those found in the literature for 2H-tetrazole derivatives. 32Nevertheless, we cannot discard a fast equilibrium between the N-1 and N-2 tautomers with the N-2 one as the main component. 33In fact, evidence of fast proton exchange is revealed by the 1 H NMR spectra, in which the tetrazole proton shows as a broad signal (9c) or was not observed (9a−b and 9d).
With all these data in our hands, the synthesis of cyanamides 8a−d and tetrazoles 9a−d was optimized.Thus, the treatment of 1a−d with a substoichiometric amount of sodium azide at 80 °C led to cyanamides 8a−d in yields ranging 25−67% (Table 5).From these data, it should be noted that the presence of a methyl group (R 1 ) next to the isocyanide group  The Journal of Organic Chemistry provided the better yields.Alternatively, the same reaction in the presence of an excess of sodium azide and longer reaction times gave tetrazoles 9a−d (39−81%).Thus, either cyanamides 8a−d or tetrazoles 9a−d can be obtained from 1a−d just by tuning the amount of sodium azide.Overall, these routes allow the access to functionalized triazoloquinoxalines, 34 compounds with interesting pharmacological properties, 35−38 without the involvement of a transition-metal 39−43 some of which are further decorated with a tetrazole ring. 44t this point, we were interested in comparing the behavior of isocyanide 1a with its isomeric cyanide (Scheme 4).Thus, 2-azidobenzonitrile was reacted with the α-ketophosphorane 6 under the usual reaction conditions to obtain the 5chloromethyltriazole 10 in excellent yield (91%).The corresponding 5-azidomethyltriazole 11 was prepared by the reaction with sodium azide in DMF at 25 °C (82%).By contrast to what we observed for 1a, the reaction of 11 in the presence of sodium azide in DMF at 80 °C for 48 h, led to the recovery of the unchanged starting material.Heating at reflux a toluene solution of 11 for 24 h was also unsuccessful for converting this azido-cyanide into its [3 + 2] cycloadduct, the tetracyclic 1,4-diazepine 12, 45−48 which however was obtained in 66% yield after heating 11 at 140 °C in DMF solution for 48 h.
Plausible mechanistic pathways for explaining the formation of cyanamides 8 from 5-azidomethyltriazoles 1 and sodium azide are outlined in Scheme 5, with 1b as the model substrate.Initially, the addition of the azide anion to the isocyanide functionality of 1b would lead to the azidoimidoyl anion 13b. 49,50Alternatively, the [3 + 2] cycloaddition between the isocyanide moiety and the azide anion could afford the tetrazolide anion 14b. 50Both anionic species, 13b and 14b, could equilibrate through an electrocyclic ring closure/ opening. 51,52The thermal activation of the experimental process (80 °C) should favor the loss of molecular nitrogen from 13b or 14b, thus leading to the carbodiimide anion 15b, which is more accurately represented as a resonance hybrid between structures 15b and the cyanamide anion 15b′.The intramolecular nucleophilic substitution of 15b with loss of the azide anion would bring about the formation of the final tricyclic cyanamide 8b.In fact, the ring fragmentation of 1-aryl-5-tetrazolyllithium derivatives at temperatures above −50 °C to give cyanamide anions has been previously reported. 53,54rom this point, the formation of 9b is easily explained through a 1,3-dipolar cycloaddition between the azide anion and the cyano group of 8b with further protonation of the resulting tetrazolide anion 16b. 25,26Two experimental facts support this mechanistic proposal, (i) only substoichiometric amounts of the azide anion are necessary to form 8b from 1b, and (ii) the quantitative formation of the tetrazole 9b cannot take place unless one equivalent of azide anion is present in the reaction mixture.
Additional alternative reaction paths leading from 13b/14b to the experimental products 8b and 9b are also summarized in Scheme 5.The intramolecular nucleophilic substitution of the azido group at the side-chain of 13b by its azidoimidoyl anionic carbon atom would afford the cyclized imidoylazide 17b, a plausible precursor of the imidoyl nitrene 18b after thermally activated loss of nitrogen.Ring expansion of this latter species by nitrene insertion would provide the cyclic carbodiimide 4b, which could also form by cyclization of 15b.A skeletal reorganization of 4b by 1,3-shift of the methylenic carbon atom could then lead to the final cyanamide 8b.Nevertheless, these latter alternative reaction pathways seem to be less plausible than that via 15b′.On the one hand, the reported formation of nitrenes from azides usually occur under FVT or photolytic conditions. 55Moreover, imidoyl nitrenes have been reported to rearrange into cyclic carbodiimides but also under photolytic conditions. 55On the other hand, the formation of cyanamides from the corresponding carbodiimides 56 has exclusively been observed by photoisomerization or pyrolysis 57,58 In order to get a deeper insight on the mechanism of the transformation of 1b into 8b, we conducted a computational study at the PCM(DMF)/WB97X-D/6-311++g(d,p)//PCM-(DMF)/WB97X-D/6-31+g(d,p) theoretical level (Figure 3).The Journal of Organic Chemistry Initially, the cycloaddition of the azide anion to 1b would lead to the tetrazolide anion 14b through the transition structure TS1 (ΔΔG = +132.0kJ mol −1 ).Alternatively, 1b could transform through the less energetic TS′1 (ΔΔG = +120.7 kJ mol −1 ), in which only one bond between the C atom of the isocyanide and the terminal N atom of the azide anion is forming, thus leading to the azidoimidoyl anion 13b (+110.5 kJ mol −1 ).However, this latter scenario is reversible and thermodynamically disfavored with respect to the formation of 14b.Subsequently, 14b loses molecular nitrogen, via the easily surmountable TS2 (ΔΔG = +53.9kJ mol −1 ), to the very stable cyanamide anion 15b.Two almost isoenergetic conformers were located for 15b, the rotamer 15b′Z being only 1.2 kJ mol −1 more stable than 15b′E (−313.8kJ mol −1 ).Each one of these rotamers is pre-oriented to undergo an intramolecular S N 2 reaction by linking either the internal N atom (15b′E) or the terminal N atom (15b′Z) of the anionic NCN fragment to the methylenic carbon atom at the side-chain, with displacement of the azide anion, respectively, leading to 8b or 4b.Thus, 15b′E would lead to the cyanamide 8b (blue dotted lines) via TS3 (ΔΔG = +134.9kJ mol −1 ) in what is the ratedetermining step of the whole reaction path going from 1b to 8b.We also located the higher energetic TS′3 (ΔΔG = +181.8kJ mol −1 ) converting 15b′Z into the cyclic carbodiimide 4b (red dotted lines), consequently discarding the putative routes leading to 8b via 4b.
The current computational study agrees well with the experimental observation of a long-lived intermediate (LLI) when the reaction was monitored by 1 H NMR spectroscopy.In fact, the computed structures for 15b′E or 15b′Z, which possess a negative charge delocalized along the aromatic ring, are in accordance with the shifts to lower frequencies experienced by the aromatic protons of LLI, detected in an early stage of the reaction (Scheme 3 and Figure 2).

■ CONCLUSIONS
Herein, we have shown a novel reaction between the azide and isocyanide functions, when both are linked to an aryl-triazolyl moiety, triggered by the action of substoichiometric amounts of sodium azide.The result is an intramolecular cyclization leading to cyclic cyanamides, which could subsequently evolve to tetrazoles by a [3 + 2] cycloaddition between its cyano group and the azide anion, providing an excess of this latter reagent is present.
These processes constitute a new instance of the metal-free reactions between the azido and isocyanide functions, in this case as an approach to complex nitrogenated heterocycles.The uniqueness of this methodology lies in the catalytic role of the azide anion to promote the formation of cyanamide derivatives.Computational studies have corroborated our mechanistic proposal initiated by the addition of the azide anion to the isocyanide functionality.Moreover, the monitoring of the reaction by means of 1 H NMR spectroscopy helped The Journal of Organic Chemistry to postulate the respective cyanamide anions as the key intermediates of these processes.The chemical behavior of our azido-isocyanides has been also compared with that of one isomeric azido-cyanide which, in contrast, only cyclized through the well-known intramolecular [3 + 2] cycloaddition between its two functionalities.In our opinion, the present work contributes to a better understanding of the reactivity between azides and isocyanides in the absence of metals.
■ EXPERIMENTAL SECTION General Methods.All reagents were purchased from commercial sources and used without further purification.HPLC grade solvents were nitrogen saturated and were dried and deoxygenated using an Innovative Technology Inc. Pure-Solv 400 Solvent Purification System.Column chromatography was carried out using silica gel (60 Å, 70−200 μm, SDS) as the stationary phase and TLC was performed on precoated silica gel on aluminum cards (0.25 mm thick, with fluorescent indicator 254 nm) and observed under UV light.All The Journal of Organic Chemistry melting points were determined on a Kofler hot-plate melting point apparatus and are uncorrected.Fourier-transform infrared (FT-IR) spectra were recorded on a PerkinElmer Spectrum 65 or JASCO FT/ IR-4700 spectrometers, and data are quoted in wavenumbers (cm −1 ).The intensities of the absorption bands are indicated as vs (very strong), s (strong), m (middle), and w (weak).NMR spectra were recorded on Bruker AVANCE 600 MHz or Bruker AVANCE 400 MHz instruments (for the latter, the operation frequency for 1 H and 13 C are 400.917MHz and 100.82MHz, respectively). 1 H NMR chemical shifts are reported relative to Me 4 Si and were referenced via residual proton resonances of the corresponding deuterated solvent, whereas 13 C NMR spectra are reported relative to Me 4 Si using the carbon signals of the deuterated solvent.Signals in the 1 H and 13 C NMR spectra of the synthesized compounds were assigned with the aid of DEPT-135.Structural assignments were made with additional information from gCOSY, NOESY, gHSQC, and gHMBC experiments.High-resolution mass spectra (HRMS) were recorded on Agilent HPLC 1200/MS TOF 6220 or Agilent HPLC 1290 Infinity II/MS Q-TOF 6550 mass spectrometers with ESI sources.The preparation of α-ketophosphorane 6 23 and 1-azido-2-isocyanoarenes 5a−d 19 was carried out by experimental procedures previously described in the literature.Azides are potentially explosive, and all reactions should be carried out behind blast shields.

Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.
Crystal data, data collection, and structure refinement for 8b; X-ray ORTEP figures; 1 H NMR monitoring of the reaction of 5-azidomethyltriazole 1b with NaN 3 in DMF-d 7 ; computed structures and theoretical 13 C NMR chemical shifts of both N-1 and N-2 tautomeric forms of 9b; NMR spectra of all new synthesized compounds; and computational methods and alternative mechanism initiated by an intramolecular [3 + 1]

Table 1 .
Synthesis of 5-Chloromethyltriazoles 7 from 1-Azido-2-isocyanoarenes 5 a After isolation by column chromatography.Scheme 2. Thermal Treatment of 7b in the Presence of NaN 3 Gives a Mixture of 1b and the Unexpected 8b

Table 4 .
Conversion Rates of 1b in the Presence of Different Amounts of NaN 3 (DMF-d 7 , 80 °C) and Ratios of 8b and 9b a a Obtained from the 1 H NMR spectra (400 MHz).b ±5% of error.